THE BIOLOGY OF POSTEROLATERAL LUMBAR SPINAL FUSION

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THE BIOLOGY OF POSTEROLATERAL LUMBAR SPINAL FUSION Scott D. Boden, MD

More than 185,000 spinal arthrodesis procedures are performed each year in the United States. Posterolateral lumbar intertransverse process arthrodesis is the most common type performed, yet failure to achieve a solid bony union (nonunion) occurs in 5% to 35% of patients with single-level fusions and more frequently when multiple levels are attempted.30,114 This high rate of nonunions indicates that the physiologic, biologic, and molecular events taht are crucial to this process are not well understood. A nonunion frequently leads to unsatisfactory resolution of clinical symptom~,2~,~, 127 and usually results in greater medical costs and morbidity,4.6,108 as well as the need for one or more additional surgeries. The most common clinical approach to prevent nonunions has been the use of internal fixation (e.g., hooks or screws, with rods or plates). Although the use of internal fixation has decreased the number of nonunions, it has not eliminated the problem; nonunions still occur in 10% to 15%of patient^.'^,^',^^^,^^ Clearly, other factors, such as biologic factors, must be implicated, yet there is a paucity of knowledge relating to the biologic mechanisms involved with the spinal fusion healing process.38,77-79 Such knowledge would be helpful in devising strategies for nonunion prevention and providing a better framework from which decisions can be made about the appropriate use

of different bone graft substitutes for posterolateral spinal fusion. This article reviews the existing knowledge base concerning the biology of spinal fusion, with the understanding that the focus is weighted toward posterolateral lumbar spinal fusion because of a relative paucity of biologic information on healing of other types of fusions. The discussion focuses first on the basic science of spinal fusion healing from the standpoint of animal modeling. Next the discussion centers on the multitude of local factors that can affect fusion healing. Finally, the numerous systemic factors known to affect fusion healing are discussed. USE OF ANIMAL MODELS TO STUDY THE BIOLOGY OF FUSION

The healing of a spinal fusion is a multifactorial process, which makes it extremely difficult to study in the clinical setting. The lack of reliable noninvasive techniques to assess the success or failure or an arthrodesis further limits clinical studies.16Thus, an animal model is a practical solution for studying individual factors involved in this complex process. Schimandle and Bodedo5examined previous animal models of spinal fusion and summarized them in a review article. Most previous models had limited utility for biologic

From the Department of Orthopaedic Surgery, Emory University School of Medicine, The Emory Spine Center, The Atlanta Veterans Affairs Medical Center, Decatur, Georgia ORTHOPEDIC CLINICS OF NORTH AMERICA VOLUME 29 hWMBER 4 OCTOBER 1998

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studies because of one or more of the following reasons: (1) The successful fusion rate was loo%, which is much higher than that seen clinically; (2) the animals used were skeletally immature, making spontaneous bone formation from periosteal stripping more likely; (3) the arthrodesis performed was interfacet or interlaminar rather than intertransverse; and (4) the model destabilized the spine and resulted in 0% successful fusions without internal fixation.75, 86, 97, 98, The limitations of these earlier models led to the development of a rabbit model that potentially was more applicable to the human situation. The major benefits of this model are the performance of a true intertransverse process arthrodesis and the occurrence of nonunions at a rate comparable to that reported in human^.^,'^^ After validation of the rabbit model, it was used to work toward two general goals. The first goal was to gain a comprehensive understanding of the lumbar intertransverse process spinal fusion with autogenous bone graft at each stage of healing. The process was characterized at each stage of healing at three levels: (1) the macroscopic level (by manual palpation, x-rays, computed tomography (CT) scans, vascular injection studies, and biomechanical testing); (2) the microscopic level (by light microscopy and quantitative histomorphometry); and (3) the molecular level (by measurement of spatial and temporal gene expression). The second goal was to use the model to gain a better understanding of the cause of nonunions by studying the effects of three inhibitory factors on spinal fusion: (1) excessive motion (a local mechanical factor) and (2) exposure to nicotine or nonsteroidal anti-inflammatory drugs (NSAIDs) (systemic biologic factors). Surgical Arthrodesis Procedure Adult New Zealand white rabbits (4.0 to 4.5 kg) or rhesus macaques (9 to 15 kg) were used. General anesthesia via subcutaneous injection may be supplemented with local anesthetic in the skin, fascia, and segmental spinal nerves. A midline skin incision was followed by two paraspinal fascia1incisions in the lumbar spine. An intermuscular posterolateral approach was used to expose the L-5 and L-6 transverse processes. The transverse processes were decorticated with an electric burr and the graft material was placed between the processes on each side. In the early experiments,

autogenous bone graft was obtained from both iliac crests at the same time, and the bone was discarded when graft materials other than autogenous bone were used. The sham harvests were stopped once it was determined that the iliac graft harvest did not affect the final outcome. For all graft materials, the volume implanted was 2.5 to 3.0 cm3per side in the rabbits and 10 to 14 cm3per side in the monkeys. In some experiments, a midline approach (rather than paraspinal) was used to facilitate performance of a laminectomy (spinal decompression) in addition to the intertransverse process arthrodesis. This was done to simulate an arthrodesis that is performed in conjunction with a posterior decompression as is common in patients with degenerative spinal stenosis. In some animals, in later experiments, a minimally invasive video-assisted percutaneous approach was used to expose and decorticate the transverse processes and place the graft material.

Goal 1: Characterization of Spinal Fusion Healing with Autogenous Bone Graft Macroscopic Analysis To characterize the lumbar intertransverse process fusion healing process, autogenous iliac crest was used as the graft material, and rabbits were euthanized at 1 to 6 or 10 weeks after surgery. Solid fusions, as determined by manual palpation, generally occurred between the third and fourth postoperative week with an overall nonunion rate of 33% (in animals at or beyond 4 weeks); waiting for the full 10 weeks did not increase the chances of fusion if the rabbit had not fused by 4 weeks. Radiographic analysis showed progressive remodeling of bone graft material with time (Fig. l), but as in humans was accurate in correctly determining whether a solid fusion was present only in approximately 70% of cases. Biomechanical strength and stiffness of the fused levels became statistically greater than that of the adjacent unfused control levels by the fourth week (P<.05). The tensile strength of the fusion masses showing nonunions was statistically less than those showing solid fusions by the fourth week (R.05). None of the control animals with omission of insertion of iliac bone graft achieved a solid fusion (Fig. 2); these negative controls showed that the surgical exposure alone did not auto-

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The rate of successful fusions in the rhesus monkey posterolateral spinal fusion model has been somewhat lower than that in the rabbit. Arthrodesis with autogenous iliac crest bone graft has yielded a 40% to 50% fusion rate, and the length of healing time was longer than in the rabbit, taking 18to 24 weeks in the monkey. When a laminectomy was performed, which resulted in some posterior destabilization, the fusion success rate with autogenous bone graft was even lower. Thus, the rhesus monkey presents an even more challenging healing environment than that of the rabbit, with a healing time similar to that assumed for human spinal fusions. Microscopic Analysis Qualitative analysis of histologic sections revealed three distinct and reproducible temporal phases of spinal fusion healing.I2The eudy phase (1 to 3 weeks) consisted of primary

Figure 1. Anteroposterior radiograph of a rabbit lumbar spine 4 weeks following posterolateralarthrodesis with autogenous iliac crest bone graft. A continuous fusion mass is seen bridging the transverse processes on each side which corresponds to a solid fusion as judged by manual palpation and the absence of motion. (from Boden SD, Schimandle JH, Hutton WC: An experimental lumbar intertransverse process spine fusion model. Spine 20:412, 1995; with permission.)

matically result in spinal fusion-a downfall of some previous models. The vascular injection studies indicated that the primary blood supply to the fusion mass originated from the decorticated transverse processes.116The failure to achieve spinal fusion in the absence of decortication emphasized the importance of extensive decortication of the lateral spine elements (lateral facet, pars interarticularis) to provide bone marrow, vascularization, and osteoprogenitor cells to the fusion mass. The performance of a true intertransverse process arthrodesis (as opposed to interlaminar or interfacet) and the occurrence of a 33% nonunion rate indicate that this rabbit model more closely mirrors the human situation than many previous models. A similar nonunion rate using autograft has also been achieved in three other laboratories that have validated this rabbit model (personal communications from DS Bradford, R McGuire, and M A ~ h e r ) . ~ ~

Figure 2. Anteroposterior radiograph of a rabbit lumbar spine 6 weeks following posterolateralarthrodesiswith autogenous iliac crest bone graft. A clear gap in the central region of the fusion mass is seen (arrowheads), which correspondedto a nonunionas judged by manual palpation and the presence of motion. (From Boden SD, Schimandle JH, Hutton WC: An experimental lumbar intertransverse process spine fusion model. Spine 20:412, 1995; with permission.)

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membranous bone formation (Fig. 3) adjacent to the decorticated transverse processes as well as conversion of the postoperative hematoma to a fibroblastic stroma around the bone graft fragments. The middle phase (4to 5 weeks) was marked by an incorporation and remodeling of bone graft fragments with a central zone of cartilage and endochondral ossification between the superior and inferior portions of the fusion mass (Fig. 4). During the late phase (6 to 10 weeks), increasing amounts of mature bone marrow were present in the fusion mass, endochondral bone formation was rare, and a rim of cortical bone formed around the periphery of the fusion mass. Quantitative histomorphometric analysis was performed to define these phases of healing at a histologic level. The early phase of healing was noted to have a ratio of cortical to cancellous bone of greater than 1.4, whereas in the late phase this ratio dropped to less than 1.O. The microscopic parameters of mean trabecular diameter, osteoid area, osteoid seam length, and percentage of trabecular surface area covered with osteoid in the fusion mass decreased initially after the surgery then returned to baseline values by 10weeks. Maturation of the spinal fusion was most advanced at

the ends of the fusion mass near the transverse processes (outer zones). A similar histologic progression occurred in the central zone but was delayed in time (Fig. 5). This central Zag effect, with a transient cartilaginous area, explains why nonunions occur in the central zone of a fusion. These central nonunions may result from mechanical disruption of the cartilaginous zone because of excessivemotion or inadequate blood supply that does not permit endochondral ossification and remodeling in the central zone. Molecular Biology Analysis

A unique temporal and spatial pattern of osteoblast-related gene expression was observed using reverse-transcriptasepolymerase chain reaction analysis of RNA from the different zones of the fusion mass (Fig. 6).” During weeks 2 and 3, a significant increase was seen in type 1collagen gene expression. Osteopontin and osteonectin were both increased by the first week, with osteopontin peaking in week 3 (150-fold increase) and osteonectin in week 2 (175-fold increase). Increased expression of osteopontin and osteonectin mRNAs was seen even at 10 weeks. A small increase in alkaline

Figure 3. Photomicrograph from a rabbit intertransverse process fusion at 3 weeks. Primary membranous ossificationwas the predominant mechanism of bone formation. Abundant unmineralized osteoid (arrowheads) could be seen on the osteoblast-lined trabeculae actively forming new bone (Goldner Trichrome, original magnification x 33). (From Boden SD, Schimandle JH, Hutton WC: An experimental lumbar intertransverse process spine fusion model. Spine 20:412, 1995; with permission.)

THE BIOLOGY OF POSTEROLATERAL LUMBAR SPINAL FUSION

Figure 4. Photomicrographfrom a rabbit intertransverseprocess fusion at 3 weeks. In the central zone of the fusion mass, where the new bone from the upper and lower transverse processes was extending, a zone of cartilage (C) and endochondral ossification (arrowheads) could be seen. (From Boden SD, Schimandle JH, Hutton WC: An experimental lumbar intertransverseprocess spine fusion model. Spine 20:412, 1995; with permission.)

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Week Figure 5. Maturation of the fusion in the rabbit intertransverse process spine arthrodesis model as measured by the area of cancellous bone (mean 2 standard error of the mean). Note the temporally more advanced fusion maturation in the “outer” zones (near the transverse processes) comparedwith the less mature fusion in the “central” zone. A similar temporal sequence of maturation occurred in the central zone, but it was delayed in time. By 10 weeks, remodeling had occurred, and the cancellous bone area was similar in both zones. (From Boden SD, Schimandle JH, Hutton WC, et al: 1995 Volvo Award in Basic Sciences. The use of an osteoinductive growth factor for lumbar spinal fusion: 1. Biology of spinal fusion. Spine 20:2626, 1995; with permission.)

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Weeks After Surgery Figure 6. Osteoblast-related gene expression during rabbit intertransverse process spine fusion is expressed as the percentage of the maximal level of expression for each gene. Using reverse transcription/polymerase chain reaction, the relative levels of gene expression were measured in the central and outer zones of rabbit spine fusion masses sequentially throughout the healing process. An orderly temporal and spatial sequence of gene expression was found.

phosphatase was seen in week 2, although this returned to baseline by week 4. A 28-fold increase in osteocalcin polymerase chain reaction product expession was seen 3 weeks after surgery in the outer zones, and this returned to baseline levels by 4 weeks. A lag effect in gene expression that correlated with the previously observed lag effect in the histologic healing sequence was noted in the central zone compared with the outer zones of the fusion. As with osteocalcin expression, the peak expression of all genes measured was seen in the central zone 1 to 2 weeks after the peak in the outer zone. This is consistent with the peripheral-to-centralhealing pattern observed histologically for fusions using autogenous bone graft. This pattern of gene expression is also similar to that observed in the hard callus portion of a healing fracture, where predominantly membranous bone formation is occurring.55,62, 102 Expression of mRNA of several bone morphogenetic proteins (BMPs) was also studied

(Fig. 7). In the peripheral zones, increased BMP-2 expressed was seen in weeks 2 through 6 with peak expression in weeks 3 and 4 (40fold increase).BMP-4 demonstrated a different pattern with a 40-fold increase in week 1 that decreased significantly by week 3. BMP-6 in the outer zones had a first peak on day 2 (54fold) and a second peak (100-fold) in week 5. BMP-6 in the central zone showed an initial peak on day 2 (34-fold) but did not demonstrate the later peak (Fig. 8). These findings suggest specific time patterns of expression and probably unique roles for the various BMPs during spinal fusion. BMP-6 appears to be somewhat unique in that its mRNA levels demonstrated the earliest peak and greatest relative increase of the BMPs studied. The lower level of BMP-6 expression in the central zone of the fusion mass is correlated with the delayed timing and smaller amount of bone formation in the central zone of the fusion. Thus, the predilection for nonunion in the central zone is apparent at a molecular biologic

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Weeks After Surgery Figure 7. Gene expression of bone morphogenetic proteins (BMP) -2, -4, and -6 during rabbit intertransverse process spine fusion is expressed as the percentage of the maximal level of expression for each gene. Using reverse transcription/polymerasechain reaction, the relative levels of gene expression were measured in the central and outer zones of rabbit spine fusion masses sequentially throughout the healing process. An orderly temporal and spatial sequence of gene expression was found with BMP-6 expression increased as early as 48 hours after surgery. Solid triangle = BMP-2; square = BMP-4; open triangle = BMP-6.

level. The expression of BMP-6 in the central zone can be enhanced by application of recombinant human BMP-2 (see Fig. 8). Goal 2: Models of Spinal Nonunion

Nonunion Caused by a Local Inhibitory Factor-Increased Motion

The purpose was to develop predictable models of nonunion to understand the normal healing process and the cause of nonunions. Rabbits underwent single-level bilateral lumbar arthrodesis at L5-6 with autogenous bone graft. They were then lifted from their cage once daily for 5 weeks; the lifting produced a transient hyperextended posture. The rabbits that were lifted exhibited a 14% fusion rate compared with a 58% fusion rate (P = .04) in control animals (i.e., those that were not lifted).39Even when the lifting protocol was

applied only for the first 2 weeks after the surgery, significantly lower fusion success rates were seen in these rabbits compared with the control animals (P = .03). The nonunion pattern was frequently a cleft through the central zone of the fusion, where the lag effect had been identified in histologic studies. Thus, a local inhibitory factor-increased motionwas able to increase the rate of nonunion in this spinal fusion model. Nonunion Caused by a Systemic Inhibitory Factor- Nicotine

Empiric clinical observations suggest that smoking (through the action of nicotine and other agents) interferes with the healing of bone fusions. Some inhibition as a result of nicotine was previously demonstrated in a model of cancellous bone graft revascularization in the rabbit distal femoral metaphysis,

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Figure 8. Comparisonof BMP-6 gene expression(measuredby reversetranscription/polymerase chain reaction)in the central and outer zones during rabbit intertransverseprocess lumbar spine fusion healing. BMP-6 expression is seen to increase in both zones as early as 48 hours following arthrodesiswith autogenousbone graft (openbars),but the level of expression falls in the central zone and is low by the 3-week time point when bone formation would be occurring centrally. Soaking of the autogenous bone graft with a solution containing recombinant human BMP-2 resulted in a greater initial increase in BMPB gene expression in the outer zones and a persistent elevation in the central zone in weeks 2 and 3, when the initiation of bone formation should occur in the central zone (solid bars).

but any negative effect brought about by the systemic nicotine was most likely lessened by the richly vascular metaphyseal healing environment.” It was hypothesized that the healing environment of a lumbar intertransverse process fusion was more challenging and that nicotine would have a noticeable effect on spinal fusion. Rabbits undergoing spinal fusion were randomized to receive a subcutaneous miniosmotic pump filled with either nicotine or saline (control). Of the control animals, 56% achieved solid spinal fusions by 5 weeks, and there were no solid fusions in the nicotine-exposed group ( P =

.O2).ll0 Serum nicotine levels were confirmed by serum radioimmunoassay testing. This experiment estalished a direct relationship between the development of a nonunion and the presence of systemic nicotine levels comparable to those seen in a moderate smoker (one to two packs per day). Thus, the same amount of systemic nicotine that dramatically inhibited healing of autogenous bone in spinal fusion had only a minimal inhibitory effect on healing of cancellous bone graft in the distal femur.% This result shows the importance of recognizing that each healing environment has unique features and that

THE BIOLOGY OF POSTEROLATERAL LUMBAR SPINAL FUSION

bone graft substitutes must be tested in the specific healing environment to predict efficacy. Nonunion Caused by a Systemic Inhibitory Factor-Ketorolac Toradol Ketorolac is commonly used as an intravenous analgesic during the postoperative period. It was determined that a standard dose (4 mg/kg/d) for 7 days resulted in a decrease in the successful fusion rate from 75% in the control group to 35% ( P < .04) in the ketorolactreated rabbits.76 Summary of Biology of Spinal Fusion Based on the Rabbit Model The discussion to this point has focused on the detailed understanding of the biology of spinal fusion obtained from the wellcharacterized rabbit model at the macroscopic, microscopic, and molecular levels. The focus of the remainder of the article is directed at summarizing the information concerning the host of local (see Table 1)and systemic factors (see Table 2) that can both positively and negatively affect spinal fusion healing. Most of these data come from less well validated animal models, human studies, and empiric teaching. LOCAL FACTORS Local factors affecting bone healing are summarized in Table 1. Table 1. LOCAL FACTORS AFFECTING BONE HEALING Positive

Negative

Good vascular supply Large decorticated host bone surface area Mechanical stability Growth factors Bone morphogenetic protein Electrical stimulation Low intensity ultrasound Physiologic mechanical loading

Radiation Tumor /marrow infiltrative disease Local bone disease Infection Mechanical instability Bone wax Denervation Inadequate volume of bone graft Bulky internal fixation

Adaptedfrom Boden SD, Schimandle JH: Biology of lumbar spine fusion and bone graft materials. In Weisel SW, Weinstein JN, Herkowitz H, et a1 (eds): The Lumbar Spine, ed 2. Philadelphia, WB Saunders, 1996, p 1285.

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Soft Tissue Bed The quality of the tissue bed into which the bone graft material is placed is of paramount importance. The entire fusion process depends on the ingress of osteoprogenitor and inflammatory cells from the recipient bed as well as the few surviving bone cells transplanted when autogenous bone is used. The tissue bed must, therefore, be able to support all processes involved in bone graft healing. These processes are greatly affected by the adequacy of the local blood supply, the efficiency of the inflammatory response, and the availability of osteoprogenitor cells. The adequacy of the blood supply in the fusion bed is a critical requisite for fusion healing. Host bed tissue must not be traumatized, and any avascular (nonviable) or traumatized tissue should be dkbrided. The fusion bed vascularity is a source of nutrients to the healing fusion, a vehicle for endocrine stimuli, and a pathway for the recruitment of inflammatory and osteoprogenitor cells, which are essential for the successful incorporation of graft material and the inhibition of infection. Hurley et al,59using a dog posterior spinal fusion model, evaluated the role played by overlying soft tissues during fusion of the spine. Thirty-seven animals underwent one of the following procedures: (1)a modified Hibbs fusion as the control procedure, (2) a Hibbs fusion with nylon-reinforced sheets of millipore (plastic membrane filter permeable to tissue fluids but impermeabze to cells) interposed between the fusion site and overlying muscle mass, or (3) a Hibbs fusion with Silastic sheets (silicone rubber impermeable to both tissue fluids and cells). All 10 L5-6 fusions with interposed Silastic sheets resulted in nonunion, whereas all 12 L5-6 fusions with interposed millipore filters resulted in a solid union. These results supported the role of the adjacent soft tissues in spinal fusion in providing a source of nutrition for migrating osteoprogenitor cells and possibly a source of diffusible growth factors. Graft Site Preparation Several methods of preparation of the bony surfaces onto which the graft material is placed are available; these include the use of a power burr, curettes, rongeurs, and osteotomes. Regardless of the technique used, the goal is to maximize the area of exposed and viable vas-

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McAfee et a1 created a dog instability model to study the effect of spinal instrumentation on achieving a successful fusion4y, 77,124 and the radiographic incidence of spinal fusion with respect to spinal 77-79 Radiographic assessment of trabecular bridging 6 months after surgery revealed a greater probability of achieving a successful spinal fusion if instrumentation was used. Nondestructive mechanical testing showed the instrumented fusions to be also significantly more rigid.49,n,78 In 1991, Zdeblick et reported a model using the Coonhound to simulate an unstable L-5 burst fracture. Use of anterior instrumentation resulted in an increased fusion rate radiographically and a more rigid fusion when biomechanically tested. Shirado et a1,lwusing this model, replicated these results. Overall the dog spinal instability/corpectomy model has proved useMechanical Stability ful in studying the in vivo response to spinal instrumentation and stabilization. Kotani The mechanical stability of the spinal et a170showed continuance of support offered segment(s) to be fused affects the rate of fuby transpedicular screw fixation in sheep ~ i o n .77-79, ~ ~ 87, , lZ4 Several studies have shown even after solid posterolateral fusions were higher union rates when internal fixation is achieved. used to decrease motion in the fusion seg4y, 77, 7x, lZ3, and when device loosening ment,14* The requirement for internal fixation may also depend on the biologic activity of the graft occurs, nonunion of the fusion mass is more material. For example, Fuller et a136,43 showed likely to O C C U Patients ~ . ~ with muscular dystrothat rigid internal fixation significantly imphy or spinal muscular atrophy have higherproved the ingrowth into a calcium carbonate than-average fusion rates, which may be the block placed in the anterior interbody thoracic result of decreased spinal segment motion and region in dogs. Ceramics are not inherently improved mechanics from decreased volunosteoinductive; they are osteoconductive and tary m ~ t i o n . ~The , " ~level of fusion (L4-5 versus rely on gradual ingrowth and revascularizaL5-S1), number of segments fused, patient's tion; thus a stable mechanical environment is weight and activity level, and use of postopercrucial. In contrast, osteoinductive bone graft ative external mobilization (bracing)lo7are all substitutes that include BMPs, may not need important mechanical factors that may influas rigid an environment for acceptable healing. ence the rate of fusion. Nagel et als7 developed an animal model In studying the effects of spinal instrumentaof delayed union and nonunion after spinal tion and biomechanical stability on the spine, fusion in sheep. Posterior lumbar laminar and most research has focused on the acute or facet fusions using iliac crest bone graft were short-term in vitro biomechanical properties of the system under s t ~ d y . 4 ~ Extrapola, ~ ~ , ~ ~ , ~performed ~ * ~ ~ ~in seven sheep. Six of seven sheep developed nonunions at the L6-Sl interspace, tion of such laboratory findings to the clinical whereas all cephalad interlumbar spaces fused use of spinal instrumentation in spinal fusions solidly (21 of 21). In vivo flexion/extension has been predicated on the information deradiographs were studied in an additional rived from this bench-top biomechanical testing eight normal sheep, and spines from five norrather than studies on the long-term in vivo mal sheep were studied ex vivo using displacebiologic effects on the fusion mass or vertebral ment transducers to determine stiffness, linear bone. The common shortcoming of these displacement, and strain of the lumbar motion bench-top studies is that the interaction besegments in flexion and extension. There was tween the biology of the fusion process and significantly more motion at the lumbosacral the instrumentation is not taken into account. level compared with other lumbar levels. This It is therefore critical to use in vivo animal finding established that motion was the major models to study the relationship between spideterminant of fusion outcome in the sheep nal instrumentation and the long-term biologic model. Similar observations about nonunions effects on spinal fusion. cular bone. Decortication using a power burr, as opposed to other methods, may induce thermal necrosis of the bone. This can be reduced by avoiding prolonged contact of the burr with the bone, using a burr with larger flutes, and using continuous irrigation. In general, the larger the surface area decorticated for fusion, the greater the availability of potential osteogenic cells and the larger the contact area exposed to support a bony bridge large enough to carry the mechanical load. Decreased surface area may be responsible for the lower fusion rates seen in patients with myelomeningocele,' although other factors may also contribute (i.e., increased infection rate, difficulty of fixation).

THE BIOLOGY OF POSTEROLATERAL LUMBAR SPINAL FUSION

at the more mobile lumbosacral junction have also been noted in dogs.59 The mechanical stresses (e.g., load, torque) experienced by the graft material itself also affect the fusion success rate.37For example, 80% of the mechanical load of a motion segment is sustained by the intervertebral disc; thus, graft material placed into an intervertebra1 body location is subjected to compressive loading. These compressive forces act on the graft and promote fusion presumedly by stimulating the ingrowth of vascular buds and proliferating mesenchymal cells from the cancellous host bone into the donor graft. In contrast, graft placed posteriorly and, to a lesser extent, in the intertransverse process area, experiences tensile forces, and healing is less favorable mechanically and more dependent on biologic factors (eg., osteogenic cells, osteoinductive factors). Even posteriorly, it has been shown in dogs that the intertransverse process fusion healing process is more challenging than the formation of bone in the interlaminar area.28 Radiation

Irradiation to a healing posterior or anterior spine fusion has an adverse effect on fusion rate and is especially detrimental within the first few weeks of fusion.13,35 This effect may be caused by direct cytotoxic effects on the migrating, proliferating, and differentiating mesenchymal or it may be related to the alteration in vascularity from both the intense vasculitis induced by the radiation injury and inhibition of angiogenesis. After the acute injury phase, radiation-induced osteonecrosis and dense hypovascular scar in the radiation bed make the fusion area a poor biologic environment for fusion; the use of vascularized grafts anastomosed to unirradiated vessels may increase the chance of successful fusion in this situation. Experimental studies of irradiated spinal fusions suggest that a delay in postoperative radiation for 3 to 6 weeks would be beneficial to the healing process. Tumor and Bone Disease

Local tumor or bone disease (e.g., fibrous dysplasia, Paget's disease) may directly invade the fusion area and replace normal marrow, structurally weakening the recipient bone and fusion mass. These obstacles can be partly overcome by using specific fixation tech-

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n i q u e ~and ~ ~by , ~appropriate ~ use of local radiation or systemic chemotherapy (or both). Use of autogenous bone graft is desirable if the prognosis is favorable, but the harvest site must be maintained as a separate surgical field to prevent tumor seeding to the donor site. Growth Factors

Several local growth factors are known to influence positively the migration, differentiation, and activity of potential bone-forming mesenchymal cells.20-22 BMP is the most widely investigated of these substances and is discussed in several reviews."', lZ1In addition to BMP, other local growth factors that influence these processes have been extracted from bone matrix and other tissues. Several of these proteins are already available through recombinant genetic technology. As the roles of these biologic mediators are elucidated, they will become an important clinical means of biologically manipulating the complex cascade of cellular events essential to the fusion 84, lo3,lo6This topic is addressed in process.10,11,25, greater detail in the article on biologic enhancement of spinal fusion elsewhere in this issue. Electrical Stimulation

Several animal and clinical studies have documented the osteogenic effect of direct current stimulation and pulsed electromagnetic fields on bone r e ~ a i r . 113, ~ ~lZ2, Most ~ ~ , studies have centered on long bone delayed unions and nonunions15, 54, 91, 93, 126 and congenital pseudarthrosis of the tibia.73, 92 Electrical stimulation has been shown to enhance the rate of spinal fusion in various animal studies4" 6s-67, 89 and human clinical tri33, 83, m, Several mechanisms of action al~.~', have been proposed; all appear to act directly or indirectly at the cellular level. Optimal biologic currents appear to be between 5 and 25 p A and can be delivered directly or via pulsed electromagnetic fields. This topic is covered in greater detail in the article on biologic enhancement of spinal fusion. Most of the clinical electrical stimulation studies were plagued with limitations, including mixed diagnoses, different fusion types, poor documentation of improved clinical outcomes, and randomization design errors. At this time, the author believes electrical stimula-

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tion may be justified for situations with impaired spinal fusion healing, but more data are needed before electrical stimulation can be recommended for routine posterolateral lumbar fusions. SYSTEMIC FACTORS

Systemic factors affecting bone healing are summarized in Table 2.

Osteoporosis Osteoporosis is the most prevalent metabolic bone disease, affecting 25 million Americans, and is commonly assumed to be a negative factor in bone healing. Although decreased bone mass is the hallmark of osteoporosis, alterations in bone marrow quality and the rate of bone turnover may also be present. The number of osteogenic stem cells in adults is 1per 100,000 marrow cells, but this ratio may be deficient in the elderly patient and, in fact, may be more important than absolute bone mass. Additionally, osteoporoticvertebrae are weak and difficult to stabilize adequately with internal fixation, especially across the mobile lumbosacral junction. All of these factors adversely affect the spinal fusion rate. Other systemic bone disorders can affect the spinal fusion healing process (see Table 2).

Table 2. SYSTEMIC FACTORS AFFECTING BONE HEALING Positive

Growth hormone/ somatomedins Thyroid hormone Vitamin A Vitamin D Insulin PTH Calcitonin Anabolic steroids

Negative

Osteoporosis Corticosteroids Vitamin D deficiency Methotrexate Doxorubicin (adriamycin) NSAIDs Smoking Anemia Rheumatoid arthritis Sepsis Diabetes Syndrome of inappropriate antidiuretic hormone secretion Malnutrition Sickle cell disease Thalassemia major

Adapted from Boden SD, Schimandle JH: Biology of lumbar spine fusion and bone graft materials. In Weisel SW, Weinstein JN, Herkowitz H, et a1 (ed): The Lumbar Spine, ed 2. Philadelphia, WB Saunders, 1996, p 1285.

Hormones Over the last decade, a considerable amount of knowledge has been gained about the control of bone formation by hormones.20These chemical messengers have complex, direct, and indirect effects on bone formation and may influence spinal fusion healing, both positively and negatively. Growth hormone has no direct effects on cartilage or bone formation but exerts its stimulatory effects through soma tome din^.^^, 96 In vivo, growth hormone stimulates bone healing by increasing intestinal absorption of calcium, bone formation, and bone mineralization.82,117 Thyroid hormones are necessary for normal growth and development. They are required for the synthesis of somatomedins by the liver104and have a direct stimulatory effect on cartilage growth and maturationlR,117 and thus have a positive effect on bone healing. Thyroid hormones act synergistically with growth hormone.l17 In both experimental and clinical situations, corticosteroids have been shown to have deleterious effects on bone healing as a result of increasing bone resorption and decreasing forhave been shown r n a t i ~ n .64~ Corticosteroids ~, both to inhibit and to promote the differentiation of osteoblasts from mesenchymal cells3,l~ and to decrease the synthesis rates of the major components of bone matrix necessary for bone healingz7 Estrogens and androgens (testosterone) are considered important in skeletal maturation of growing individuals and in the prevention of the bone loss associated with aging. The in vivo effects of these hormones on bone healing, however, are controversial. Although some studies indicate that they may stimulate bone formation? most do not support this possibilit^.^^,'^ In vitro studies have shown that neither estrogens nor androgens affect bone collagen but estrogens may increase bone mineralization by increasing serum parathyroid hormone and vitamin D3concentrations." Nutrition

Nutritional status has been shown to affect bone healing in the orthopedic patient.%, If suspected, nutritional deficienciescan be identified using serum albumin and transferrin levels, total lymphocyte count, skin-antigen testing, anthropometric measurements, and nitrogen balance studies. These studies can be

THE BIOLOGY OF POSTEROLATERAL LUMBAR SPINAL FUSION

useful in assessing the nutritional status of selected patients to determine the need for nutritional support. Hematologic disorders, such as sickle cell disease and thalassemia major, may also decrease the osteogenic potential of bone marrow by overgrowth of the hematopoietic elements at the expense of the osteoprogenitor cells. Iron deficiency anemia impairs fracture healing'O' and similarly may adversely affect fusion consolidation.

Drugs Certain drugs taken during the perioperative period can inhibit or delay bone formation. NSAIDs (e.g., ibuprofen, indomethacin, and ketorolac) suppress the inflammatory response but may inhibit bone formation and spinal fusion.31~45,56,58,74 In addition, chemotherapeutic agents, such as methotrexate and doxorubicin (Adriamycin),inhibit bone formation and healing if administered early in the postoperative peri~d.'~,90, 94

Smoking Cigarette smoking interferes with bone metabolism and revascularization and inhibits bone formation. Extracts from tobacco smoke have been reported to induce calcitonin resistan~e,5~ increase bone resorption at fracture ends," and interfere with osteoblastic functi~n.~O The rate of nonunion in smokers after spinal fusion has been shown to be higher than that in nonsmokers.8,17, 51, lz3

KNOWLEDGE GAPS AND FUTURE RESEARCH DIRECTIONS In 1990, when the author began studying the existing literature on the biology of spinal fusion, it became clear that there were large voids in basic understanding of this multifactorial process. At that time, basic questions were unanswered, such as: What type of healing (endochondral or membranous) occurred during fusion consolidation? Does the bone graft develop adequate blood supply from the surrounding muscles? Do systemic inhibitory factors such as nicotine or NSAIDs inhibit spinal fusion healing? What molecular signals trigger the initiation of the normal healing process, and what is the sequence of gene expres-

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sion during spinal fusion healing? Do growth factors, such as BMPs, play a role in spinal fusion healing? Are some growth factors more important, or are they all interchangeable? Since that time, the dedication of many individuals in the author's laboratory and in others has begun to focus on obtaining this type of critical biologic information. It is known that the initial healing mechanism is membranous bone formation with a short phase of endochondral ossification in the center of the fusion mass. It is known that the surrounding muscles are not adequate to nourish a new fusion. Additionally,the decorticatedhost bone is critical to influx of cells and blood supply, which results in the fusion healing first near the decorticated surfaces and last in a central watershed zone. It is known that nicotine and some NSAIDs significantly inhibit spinal fusion healing, at least in part, through inhibiting revascularization of the bone graft. We have begun to learn the spatial and temporal pattern of gene expression of the basic osteoblastand cartilagerelated genes. In addition, evidence suggests that specific BMPs may play important roles as early as 48 hours after fusion begins, whereas others may not be expressed for several weeks. This pattern suggests that all BMPs may not be interchangeable,and some may be more appropriate depending on the type of bone formation being initiated and the local environment. These answers serve only as a beginning to an adequate understanding of the process to permit clinicians to manipulate the process at will with the osteoinductive proteins that will soon be commercially available as well ,as the techniques of gene therapy, which have been infiltrating many medical subspecialties. There is a growing trend to expand the longstanding focus in spine research on biomechanics and internal fixation toward understanding and ultimately controlling the biology of spinal fusion. Although some clinicians may believe that this knowledge has little to do with their surgical technique in the operating room today, they should take heed as this type of information may define the way they perform their fusion procedures and what graft materials they may use in the future. Such information is critical if clinicians are to optimize the use of the new osteoinductive bone growth factors, which have the potential to eliminate the morbidity of autogenous bone graft and improve the healing success. ACKNOWLEDGMENTS Many individuals played vital roles in this ongoing project, and without them this work would not have been

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possible: Thomas E. Whitesides, MD; John G. Heller, MD; William C. Horton, MD; D. Hal Silcox 111, MD; Howard I. Levy, MD; Susan Dreyer, MD; Michael Chen, MD; Gregory Riebel, MD; Michael Feiertag, MD; Yasumitsu Toribatake, MD; J o h nUgbo, MD; Peter Moskovitz, MD; John Wozney, PhD; Anthony Celeste, PhD; James Benedict, PhD; Chris Damien, PhD; Nelson Scarborough, PhD; Bill McKay; Cynthia Baranowski; Suzanne Collier; Mela Freedman; Eunice Threadcraft; Gregory Hair, PhD; Louisa Titus, PhD; Michelle Racine; Kimberly McCuaig; Yunshan Liu, PhD; and Thelma Snider.

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Address reprint requests to Scott D. Boden, MD The Emory Spine Center 2165 North Decatur Road Decatur. GA 30033